Nature Communications reports a selenium-based metabolic oligosaccharide engineering strategy by Ran Xie’s group


Glycans play crucial roles in various biological activities in living systems. Intercellular communications and cancer cell activities are usually accompanied by dynamic turnover and perturbation of newly synthesized glycans. However, dynamic subtle glycan changes are still difficult to be captured and absolutely quantified, due to challenges in glycan characterization and quantification.

Nowadays, metabolic oligosaccharide engineering (MOE) is a classical chemical approach to perturb, profile and perceive glycans in physiological systems. Metabolic precursors/analogues are metabolically activated and incorporated into the glycomes. In a second step, modification with bioorthogonal functionalities, can be probed by bioorthogonal reactions, to allow for the dynamic and versatile glycan visualization, as well as glycoconjugate isolation and -omic analysis. However, one major limitation of MOE has been the lack of quantitative glycan measurement. Additionally, maneuvering MOE and installing the incorporated bioorthogonal functional groups with alternative signal output modalities, such as 1,2-diamino-4,5-methylenedioxybenzene (DMB), Europium (Eu) isotopic mass-tag and surface-enhanced Raman spectroscopy (SERS) probe, have allowed for the detection and quantification of monosaccharide derivates. Nevertheless, the stoichiometric attachment of complementary probes to glycoconjugates is inevitably hampered by their accessibility, and the non-specific interactions between added probes and cellular components additionally increased the difficulty of quantitative readouts. Therefore, developing a simple, safe and sensitive quantification methodology for glycan detection is necessary.

As a trace element in the human body, selenium can be effectively quantitatively analyzed and imaged using elemental analysis techniques such as inductively coupled plasma mass spectrometry (ICP-MS). Its background level in biological organisms is close to the detection limit. Additionally, selenium displays distinct isotopic distribution characteristics in mass spectrometry, making it a promising candidate for selenium-targeted proteomics analysis.

Based on this, Prof. Ran Xie from our department, and Prof. Meng Wang from the Institute of High Energy Physics of the Chinese Academy of Sciences, have recently reported a selenium-based metabolic oligosaccharide engineering strategy (SeMOE) in Nature Communications. This strategy introduces selenium methyl groups into the acetylamino side chains of sugar precursors such as sialic acid, glucosamine, and galactosamine, thereby constructing a series of selenium-substituted non-natural sugars. Additionally, the authors have designed and synthesized bifunctional sugars containing both Se and azido groups, which, combined with MOE, allow for the labeling of Se atoms on glycans. Furthermore, multiple-dimensional detection of glycans, including quantitative analysis, visualization, and glycomics analysis, has been achieved through various techniques such as ICP-MS, mass spectrometry flow cytometry, confocal microscopy, and biomolecular mass spectrometry (Fig.1). Compared to the traditional MOE, SeMOE avoids the secondary reactions and exhibits extremely low detection limits, ideal sensitivity, and excellent signal-to-noise ratio, enabling precise quantification and multi-dimensional detection of glycans, particularly newly synthesized glycans.


Fig.1. Schematic of SeMOE methodology (a) and SeMOE probes in this study (b)

The authors conducted a comprehensive and systematic evaluation of the safety, effectiveness, sensitivity, and specificity of SeMOE probes. They tracked and quantitatively analyzed the dynamic changes and fate of newly synthesized glycans at the single-cell, subcellular, and biomacromolecular levels. SeMOE was also applied in glycoproteomic analysis and targeted glycomics analysis. Moreover, the authors focused on the glycan transfer in different cell-cell interaction models. This allowed them to capture and quantify the dynamic transfer and sharing of glycans between cells at the attomolar level for the first time. Additionally, SeMOE was employed for in situ imaging and quantification of glycans in diverse mouse tissues. Selenosugars also exhibit anti-cancer potential, which warrants further development and research.

To sum up, the introduction of SeMOE, an innovative and simplified method, into chemical glycobiology, will augment a more accurate interpretation of glycans in biophysiological and therapeutic events. Methodological adaption from chemoenzymatic glycan labeling or Se-click reaction will integrate the enrichment and quantification of glycoconjugates, which doubtlessly provide room for methodological improvement. In addition, if the SeMOE analogs were synthesized as Se-isotopically enriched derivatives, these probes are readily distinguished by ICP-MS and may find broader applications in temporal studies. These concepts are being pursued in Ran Xie’s group.

The related paper entitled “Selenium-based metabolic oligosaccharide engineering strategy for quantitative glycan detection” was published in Nature Communications on December 13th, 2023 (DOI: Ran Xie from our school and Prof. Meng Wang from the Institute of High Energy Physics of Chinese Academy of Sciences are the corresponding authors. Ph.D. student Xiao Tian from our department is the first author. This project was funded by the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province, the Chinese Academy of Sciences, the Beijing Natural Science Foundation, the Programs for High-level Entrepreneurial and Innovative Talents Introduction of Jiangsu Province (Individual and Group Program), the Fundamental Research Funds for the Central Universities, the STI2030-Major Projects, and the National Key R&D Program of China.